Genetic Variant EIF2B1:p.Phe239Leu (chr12-123622674-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The ENST00000424014.7(EIF2B1):c.715T>C(p.Phe239Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F239V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

EIF2B1
ENST00000424014.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.30

Publications

1 publications found

Variant links:

Genes affected

EIF2B1 (HGNC:3257): (eukaryotic translation initiation factor 2B subunit alpha) This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Oct 2009]

EIF2B1 Gene-Disease associations (from GenCC):

leukoencephalopathy with vanishing white matter
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
leukoencephalopathy with vanishing white matter 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ovarioleukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EIF2B1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-123622674-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 217282.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000424014.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	NM_001414.4	MANE Select	c.715T>C	p.Phe239Leu	missense	Exon 8 of 9	NP_001405.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EIF2B1	ENST00000424014.7	TSL:1 MANE Select	c.715T>C	p.Phe239Leu	missense	Exon 8 of 9	ENSP00000416250.2
EIF2B1	ENST00000539951.5	TSL:5	c.600T>C	p.Ser200Ser	synonymous	Exon 6 of 7	ENSP00000438060.1
EIF2B1	ENST00000534960.5	TSL:5	c.*122T>C		3_prime_UTR	Exon 6 of 6	ENSP00000443172.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.5

PhyloP100

9.3

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.58

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0060

Polyphen

0.86

Vest4

0.57

MutPred

0.50

Gain of catalytic residue at F235 (P = 0.0305)

MVP

0.98

MPC

0.70

ClinPred

0.99

GERP RS

6.2

Varity_R

0.91

gMVP

0.91

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over